TY - JOUR
T1 - Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles
AU - VA Million Veteran Program
AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
AU - Huffman, Jennifer E.
AU - Nicholas, Jayna
AU - Hahn, Julie
AU - Heath, Adam S.
AU - Raffield, Laura M.
AU - Yanek, Lisa R.
AU - Brody, Jennifer A.
AU - Thibord, Florian
AU - Almasy, Laura
AU - Bartz, Traci M.
AU - Bielak, Lawrence F.
AU - Bowler, Russell P.
AU - Carrasquilla, Germán D.
AU - Chasman, Daniel I.
AU - Chen, Ming Huei
AU - Emmert, David B.
AU - Ghanbari, Mohsen
AU - Haessler, Jeffrey
AU - Hottenga, Jouke Jan
AU - Kleber, Marcus E.
AU - Le, Ngoc Quynh
AU - Lee, Jiwon
AU - Lewis, Joshua P.
AU - Li-Gao, Ruifang
AU - Luan, Jian'an
AU - Malmberg, Anni
AU - Mangino, Massimo
AU - Marioni, Riccardo E.
AU - Martinez-Perez, Angel
AU - Pankratz, Nathan
AU - Polasek, Ozren
AU - Richmond, Anne
AU - Rodriguez, Benjamin A.T.
AU - Rotter, Jerome I.
AU - Steri, Maristella
AU - Suchon, Pierre
AU - Trompet, Stella
AU - Weiss, Stefan
AU - Zare, Marjan
AU - Auer, Paul
AU - Cho, Michael H.
AU - Christofidou, Paraskevi
AU - Davies, Gail
AU - de Geus, Eco
AU - Deleuze, Jean François
AU - Delgado, Graciela E.
AU - Ekunwe, Lynette
AU - Faraday, Nauder
AU - Gögele, Martin
AU - Greinacher, Andreas
N1 - Publisher Copyright:
© 2024
PY - 2024/11/21
Y1 - 2024/11/21
N2 - Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.
AB - Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.
UR - https://www.scopus.com/pages/publications/85207137131
U2 - 10.1182/blood.2023022596
DO - 10.1182/blood.2023022596
M3 - Article
C2 - 39226462
AN - SCOPUS:85207137131
SN - 0006-4971
VL - 144
SP - 2248
EP - 2265
JO - Blood
JF - Blood
IS - 21
ER -